Abstract: Type 2 diabetes mellitus (T2DM) affects approximately 25.8 million Americans and consumes more than $210 billion dollars in United States health care costs every year. T2DM is a polygenetic and chronic disease, involving insulin resistance and ? cell dysfunction. However, only 40-50% of individuals with insulin resistance progress to T2DM. The pivotal defect in those who progress is that ? cells fail to compensate for the insulin resistance with appropriate hyperinsulinemia, become dysfunctional and, eventually, die. Thus, ? cell dysfunction is a key step in the progression from metabolic impairments to a disease state. Another big question in T2DM is whether T2DM is reversible. Bariatric surgery has been shown to induce remission in a high proportion of severely obese patients with T2DM. Additional data suggested ? cell function improves after bariatric surgery. However, how environmental and genetic factors affect the progression and regression of ? cell dysfunction is largely unknown. Thus, there is a strong need to establish novel models to study the progression and regression of ? cell dysfunction in T2DM. Human induced pluripotent stem cells (hiPSCs), provide new systems to study the genetic factors in human diseases, as well as a platform to recapitulate the cellular pathology in the diseases. However, hiPSCs have not yet been successfully used to model chronic diseases. Here, we propose to use humanized mouse models to study the role of the environmental and genetic factors in the progression and regression of ? cell dysfunction in T2DM. By collaborating with New York Organ Donation Network, we collect islets from healthy donors, donors diagnosed with insulin resistance or donors diagnosed with T2DM. We use two approaches to create humanized mice. One is to directly use the primary patient islets. The other one is to establish iPSCs from patient islets and create humanized mice using iPSCs-derived endocrine progenitors. The proposed study is truly innovative because it establishes a model to use iPSCs to study a chronic disease affected by both environmental and genetic factors. Compare to the previous studies using patient population or animal models, the humanized mouse models have several advantages. Firstly, the models using patient islets or glucose-responding cells derived from patient-specific iPSCs, which carry the genetic defects of patients. Secondly, the environmental factors in a humanized mice model can be tightly controlled. Finally, humanized mice containing patient-specific iPSC-derived population provide a platform to real time monitor the progression of ? cell dysfunction from compensation to dysfunction, and finally apoptosis. We will use these humanized mouse models to study the effect of environmental and genetic factors on the rate and dynamic of the progression and regression of ? cell dysfunction, and identify the tipping point of the progression of ? cell dysfunction of T2DM. The proposed study has high impact because we will learn how to prevent or treat T2DM.